Substituted salicylonitriles

ABSTRACT

A process for the preparation of a cyanophenol of formula (I)   wherein Z is a substituent in the 4- or 6- position with respect to the hydroxy group, characterized in that cyanide ions are reacted in a dipolar aprotic solvent with a nitrobenzene of formula (II)   wherein Z has the same value as in formula (I) and is a group, other than a nitro group, known to withdraw electrons in substitution reactions and which does not contain a proton capable if ionizing under the defined reaction conditions if such ionization would inhibit the electron-withdrawing effect of the group Z. In formula (I) and (II) the benzene ring is optionally substituted by one or more non electron-withdrawing groups, or by one or more electron-withdrawing groups provided that such electron-withdrawing groups are in positions other than the 4and 6- positions with respect to the hydroxy group. The compounds of formula (I) are of value in being readily hydrolysed to the corresponding salicylic acids of formula (III)   certain of which have been described in the literature as possessing a variety of pharmacological properties.

United States Patent [1 1 Gorvin (451 Aug. 26, 1975 54 l SUBSTITUTED SALICYLONITRILES [75] Inventor: John Henry Gorvin, London,

England [73] Assignee: Burroughs Wellcome & C0. (U.S.A.)

Inc., Research Triangle Park, NC.

22 Filed: Feb. 15, 1974 21 Appl.No.:442,8l6

Related U.S. Application Data [62] Division of Scr. No. 255,186, May I9, 1972,

abandoned.

[30] Foreign Application Priority Data May 21, 1971 United Kingdom l6l97/7l [52] U.S. Cl..." 260/465 F; 260/279 R; 260/293.75; 260/294.9; 260/297 R; 260/332.3 R;

260/335; 260/465 R; 260/465 D; 260/47l R; 260/517; 260/52] R; 260/59l; 260/607 A;

260/646 [5|] Int. Cl. C07C 121/52 [58] Field of Search 6. 260/465 F [56] References Cited OTHER PUBLICATIONS J. Chem. Soc. D. (i971) pages ll20-l l2| Gorvin. C. A. 59: 38l0 h (I963) Aleksandcr Primary ExaminerHenry R. Jiles Assistant Examiner-S. D. Winters Attorney, Agenl, or FirmDonald Brown [57] ABSTRACT A process for the preparation ofa cyanophenol of formula (I) wherein Z is a substituent in the 4- or 6- position with respect to the hydroxy group, characterized in that cyanide ions are reacted in a dipolar aprotic solvent with a nitrobenzene of formula (II) wherein Z has the same value as in formula (I) and is a group, other than a nitro group, known to withdraw electrons in substitution reactions and which does not contain a proton Capable if ionizing under the defined reaction conditions if such ionization would inhibit the electron-withdrawing effect of the group Z.

The compounds of formula (I) are of value in being readily hydrolysed to the corresponding salicylic acids of formula (Ill) COOH CH (III) certain of which have been described in the literature as possessing a variety of pharmacological properties.

4 Claims, No Drawings SUBSTITUTED SALICYLUNITRILES This application is a division of U.S. application Ser. Nov 155186, filed May l). [972, now abandoned.

This invention relates to cyanophcnols and their preparation and to their conversion to salicylic acids.

More particularly, the present invention relates to a novel process for the preparation of 2-cyanophcnols of formula ill I wherein Z is a substituent in the 4- or 6 position with respect to the hydroxy group and is a group, other than a nitro group, known to withdraw electrons in substitu tion reactions.

The novel process provided by the present invention for the preparation of the compounds of formula (1) comprises the reaction in a dipolar aprotic solvent of cyanide ions with a nitrobenzene of formula (ll) wherein Z has the same meaning as in formula (l). in the course of the reaction a substituent cyano group is attached to the benzene ring in the 2- position to that occupied by the nitro group, which latter is itself re placed by an hydroxy group.

Provided by formula (I) are those compounds wherein Z is a cyano group, a trifluoromethyl group, or a group Y.X wherein X is the carbonyl or sulphonyl group and Y is a group which does not contain a proton capable of ionising under the conditions as herein described of the synthesis of the compounds if such ionization would inhibit the electron-withdrawing effect of the group X.

Thus Y may be a saturated aliphatic hydrocarbon group (for example an alkyl group such as a lower alkyl group having 1 to 4 carbon atoms);

an alkoxy group (for example a lower alkoxy group having I to 4 carbon atoms, such as an ethoxy group);

an aryloxy group (for example a phenoxy group);

an aromatic nucleus (for example a phenyl or naph thyl group);

a heteroaromatic nucleus (for example a xanthonyl, phenoxathiinyl. pyridyl furanyl. thienyl, N-(|ower alkyl)pyrrolyl or quinolyl group);

a disubstituted nitrogen atom (for example a pyrrolidino, piperidino or morpholino group, or a tertiary amino group such as a diarylamino, dialkylamino or N-alkyl-Narylamino group where the alkyl" is for example a lower alkyl having 1 to 4 carbon atoms and the aryl is for example pncnyl); or

a or t rntrmbcred llfifl til'tlllltillt cyclic or heterocyclic system having no proton ioniaable in the manner defined above;

where Y i optionally joined to the benzene ring in formula (I I either directly or by a methylene, carbonyl, oxy, tliio, sulphinyl or sulphonyl group. or by a mo noulltylatnino group where the alkyl is preferably a lower alltyl having l to 4 carbon atoms. and where Y, except when saturated aliphatic hydrocarbon alkoxy or dialkylamino, is optionally substituted by one or more groups selected from halogen (chlorine, bromine, fluorine and iodine);

aryl (for example phenyl, halogenophenyl, xylyl, salicyl and tolyl);

aryloxy (for example phenoxy);

alkoxy (for example lower alkoxy having l to 4 car bon atoms, such as methoxy, ethoxy, isopropoxy and butoxy);

cyano',

trifluoromethyl',

And the groups C(J.W and --SO .W where W has the same meaning as Y as hereinabove defined,

With the proviso that, when Y is N-alkyLN arylamino only the aryl moiety may be substituted in the above defined manner.

Further, in formulas l) and (Il) the benzene ring can optionally be further substituted by one or more nonelectron withdrawing groups, such as halogen where the halogen is for example chlorine. As another possi' bility the benzene ring can optionally be substituted by one or more additional electron-withdrawing groups, such as those hereinbefore described, provided that said electr-on'witbdrawing groups are in positions other than the 4- and (i-positions with respect to the hydroxy group,

As a preferred class within formula (I) are those compounds having no further substitution in the benzene ring and wherein Z is a cyano group or a group Y.X- wherein X is the carbonyl or sulphonyl group and Y is selected from N-phcnyLN-(lowcr alkyl)amin0, furanyl, thienyl, N-(lower alkyl)pyrrolyl, cyclopeutadienyl and phenyl. where the phenyl is optionally joined to the benzene ring in formula (I) either directly or by a methylene, carbonyl, thio, sulphinyl, sulphonyl, oxy or rnonoalkylarnino group, and wherein Y is optionally substituted by one or more groups selected front halogen. aryl, aryloxy, alkoxy, cyano, trifluoromethyl and carboalkoxy, for example carbomethoxy and carboethoxy. The hydroxyisophthalie acids corresponding to those compounds of formula (I) wherein Z is a cyano group have been described possessing antipyretic and analgesic properties (Brit. J. PharmaroL, (1 56), 11,20; Narurdlcondonl, H953 l75, 206, The salicylic acids and the salts thereof corresponding to the remainder of this preferred class of compounds within formula (I) have been described as possessing antiintiatnmatory activity and as also showing analgesic, anti-t'ibrinolytie, anti-pyretic, diuretic and hypoglycaenric properties (Dutch Patent Nos. 70081521; 70.08622; 70.08627; 70.08628; 70.08629; 70.08631; 7098636; and 70.08637).

As a second preferred class within formula (I) are those compounds having no further substitution in the benzene ring and wherein is a cyano group or a group YX wherein X is the carbonyl or sulphonyl group and r is selected from alltoxy, phenoxy. an aromatic nucleus, at helcroaromatic nucleus ta itanthonyl, pheioxathiinyl, pyridyl or quinolyl group) and a disubstiuted nitrogen atom, wherein Y is optionally joined to he benzene ring in formula (I) either directly or by an my or monoalkylamino group, and wherein Y is opionally substituted by one or more groups selected rom cyano, halogen, trifluoromethyl, aryl, phenoxy ind alkoxy and the groups CO.W and SO,.W vhere W has the same meaning as Y as hereinabove deined.

As a third preferred class within formula (I) are those ompounds having no further substitution in the henene ring and wherein Z is a cyano group or a group .X- wherein X is the carbonyl or sulphonyl group nd Y is selected from N-phenyl-N-(lower alkyl)amino nd phenyl, wherein the phenyl is optionally joined to he benzene ring in formula (I) either directly or by an xy or monoalkylamino group, and wherein Y is opionally substituted by one or more groups selected rom halogen, trifluoromethyl, aryl, phenoxy, alkoxy, yano, and carboalkoxy, for example carbomethoxy nd carboethoxy. The hydroxyisophthalic acids correponding to those compounds of formula (I) wherein Z a a cyano group has been described as possessing antiyretic and analgesic properties (references as above) 'hilst the salicylic acids and the salts thereof corre Jonding to the remainder of this preferred class of ompounds within formula (I) have been described as ossessing anti-inflammatory activity and as also showig analgesic, anti-fibrinolytic. anti-pyretic, diuretic nd hypoglycaemic properties (Dutch Patent Nos. 008621;, 70.08627; 70.08628; 70.08629; 70.0863l; nd 70.08636).

For the preparation of the compounds of formula I) the above-described manner the reagents are prefer- Jly anhydrous, this being especially critical where iere are present in the compounds of formula (ll) hyrolysable groups such as ester groups.

Suitable solvents include dimethylsulphoxide, diethylformamide, hexamethylphosphoramide, dimethacetamide, hbmethyl-Z-pyrrolidone, sulfolane, acetotrile and mixtures thereof. The cyanide ions are con- :niently provided by an ionisable cyanide salt which also soluble in the solvent chosen, an alkali metal cylide such as sodium cyanide or potassium cyanide :ing suitable.

It will be appreciated that the optimum reaction tem- :rature will depend upon the particular compound of rmula (ll) concerned. Any temperature up to the retx temperature of the reaction mixture may be emoyed but. having regard to this figure, a temperature between 50 and ISOC. is preferred and a temperare of between 80 and [20C. is most preferred.

In the course of the reaction azo and azoxy byoducts are produced which may be readily removed .ring the purification of the cyanophenol.

As indicated above, certain of the salicylic acids of rmula (lll) 0 (III) and the salts thereof, wherein Z has the same meaning as hereinabove, have been variously described as showing analgesic, anti-fibrinolytic, antiinflammatory, antipyretic, diuretic and hypoglycaemic activity.

Heretofore, compounds of formula (ll) and the salts thereof have been conventionally prepared by carboxylation of the corresponding phenol using carbon dioxide at high temperatures and superatmospheric pressures, and the phenol is itself generally prepared only by means of a multi-stage process. These disadvantages are avoided if the compounds of formula (lll) are prepared by hydrolysis of the cyanophenols of formula l), the latter being obtained in the manner indicated above from the readily synthesised nitrobenzenes of formula (II). The hydrolysis may be effected under either acid or alkaline conditions; for acid hydrolysis 60% sulphuric acid or a hydrohalide acid such as concentrated hydrochloric acid is a suitable agent, and for alkaline hydrolysis an aqueous alkali such as 25% aqueous sodium hydroxide may be used. The compounds of formula (lll) may be isolated either as such or as a salt thereof.

The present invention therefore provided a process as hereinbefore described for the preparation of the compounds of formula (I), the novel compounds of formula (l), the known compounds of formula (1) when prepared by the process as hereinbefore described, a process as hereinbefore described for preparing the compounds of formula (III) and the salts thereof from the compounds of formula (I), and the compounds of formula (III) and the salts thereof when so prepared.

The following Examples illustrate the present invention, all temperatures being in degrees Celsius.

EXAMPLE I trate was extracted with ether and the 5- benzoylsalicylonitrile thus obtained was crystallised from aqueous ethanol to give needles, m.p. l-l86C.

b. By a similar method 4-methoxy-4- nitrobenzophenone was converted into S-p-methoxybenzoylsalicylonitrile, m.p.I67-l68C. (after loss of 1 molecule of water of hydration).

EXAMPLE 2 a. A mixture of p-nitrodiphenylsulphone [3.2g.) and dry powdered potassium cyanide (10g) in dimethylsulphoxide (100 ml.) was heated for 3% hours at l00C. The solution was diluted with a large volume of water and the precipitate collected by filtration. This solid was treated with a mixture of l0% aqueous sodium hydroxide (200 ml.) and 10% aqueous sodium carbonate (50 ml.) and the insoluble solid filtered off. On acidification of the filtrate with hydrochloric acid there was obtained S-benzenesulphonylsalicylonitrile which gave hydrated crystals (from ethanol), m.p. l-l96C.

b. By a similar procedure 4-chloro-4'- nitrodiphenylsulphone was converted to 5-pchlorobenzenesulphonylsalicylonitrile, which formed hydrated crystals (from ethanol) m'pv 92C. and 205207C.

EXAMPLE 3 av A mixture of 3-nitroxanthone (1.44g.) and powdered potassium cyanide (3.0g) in dimethylformamide (50ml.) was heated at 100C. for 4 hours. after which time water was added and the insoluble precipitate removed. Acidification gave 3-hydroxyxanthone-4- carbonitrile which from aqueous ethanol gave crystals containing 1 molecule of water of crystallisation and having m.p. 304305C.

b. In a similar manner N-methyl-B-nitroacridone was converted to 3-hydroxy-N methylacridone 4- carbonitrile (m.p.3lC.).

EXAMPLE 4 a. p-Nitrobenzonitrile (14.8g.) was heated at 100C. in dimethylsulphoxide (70 ml.) with dry powdered potassium cyanide (20g) for 2 hours. The mixture was poured into water and an insoluble precipitate removed. Acidification of the filtrate and extraction with ether gave 2,4-dicyanophenol (did not melt but changed form at 240C); on hydrolysis with concentrated hydrochloric acid this compound gave 4- hydroxyisophthalic acid. m.p. 3 l0C.

b. Similarly, from o-nitrobenzonitrile was prepared 2.6-dicyanophenol which on hydrolysis with concentrated hydrochloric acid gave 2-hydroxyisophthalic acid, m.p.(monohydrate)245C..

EXAMPLE 5 a. Ethyl p-nitrobenzoate (l.95g.) was heated in dimethylsulphoxide (l5 ml.) with dry powdered potassium cyanide (2g) at l lOl20C. for 3% hours. The solution was poured into water and acidified. The filtered solid was shaken with aqueous sodium carbonate containing some sodium hydroxide, filtered and acidified. The crystals obtained on standing were recrystallised from hot water to give ethyl 3-cyano-4- hydroxybenzoate, m.p. l92-l93C., which was hydrolysed with concentrated hydrochloric acid to yield 4- hydroxyisophthalic acid, m.p. 310C.

b. By treating N-p-nitrobenzoylpiperidine in a similar manner was obtained N-(3-cyano-4-hydroxybenzoyl)- piperidine, which on hydrolysis with concentrated hydrochloric acid gave 4-hydroxyisophthalic acid, m.p. 310C.

EXAMPLE 6 4-(p-Nitrobenzoyl)pyridine (CfBryans and Pyman, J. Chem. Soc. 1929, 552) 1.04g.) was heated with potassium cyanide (1.0g.) in dimethylsulphoxide (20 ml.) at C. for 3% hours. The solution was poured into water and the precipitated material removed by addition of charcoal and filtration of the suspension through kieselguhr. The filtrate was neutralized (pH6-7) and the precipitated solid collected. Crystallisation from ethanol gave 4-(3-cyano4-hydroxyben zoyl)pyridine. m.p. 3l03l |C.

EXAMPLE 7 2-p-Nitrobenzoylthiophene (2.33 g.) was allowed to react with potassium cyanide (3.9 g., 6 mols) in dimethyl sulphoxide (40 ml.) at IO0C for 3% hours. The solution was poured into water and the cloudiness removed with charcoal. The clear filtrate gave a precipitate on acidification; this was collected and crystallised from aqueous ethanol to give 2-(3-cyano-4- hydroxybenzoyl)thiophene, m.p. 216.C

EXAMPLE8 2-Nitro-a,a,a-trifluorotoluene (3.82 g.) was heated at 100C for 3 hours with potassium cyanide (7.8 g.) in dimethyl sulphoxide (40 ml.). After pouring into water. the mixture was brought to pH 7 and filtered. Acidifcation, ethe'r extraction, and removal of the ether gave a solid which was sublimed or crystallised from aqueous ethanol to give 3trifluoromethyl-salicylonitrile, m.p. 134C.

EXAMPLE 9 Using a method similar to that of Example I, 3chloro-4-nitrobenzophenone was converted by potassium cyanide in dimethyl sulphoxide into 3-chloro- 5-bentoylsalicylonitrile, which crystallised from aqueous ethanol as the monohydrate, m.p. C.

EXAMPLE 10 4. 3-Chloro-5benzoylsalicylonitrile. 

1. 5-P-METHOXYBENZOYLSALICYLONITRILE.
 2. 5-Benzenesulphonylsalicylonitrile.
 3. 5-p-Chlorobenzenesulphonylsalicylonitrile.
 4. 3-Chloro-5-benzoylsalicylonitrile. 